Platelet Disorders

Platelet biology (granules and function)

• Normal hemostatic sequence:
  • Adhesion: platelet binds subendothelial vWF and collagen via GPIb-IX-V (vWF) and GPVI (collagen).
  • Activation: shape change exposes GPIIb/IIIa receptors; granule release.
  • Aggregation: cross-linking of activated GPIIb/IIIa by fibrinogen (and vWF) bridges platelets.
  • Propagation of coagulation: activated platelets provide an anionic phospholipid surface for assembly of procoagulant enzyme complexes.

Diagnostic approach

• Platelet count + smear: first step, rule out pseudothrombocytopenia. Assess platelet size and granularity, review RBC morphology (schistocytes) and WBC morphology (infection, MYH9 inclusions, blasts). MPV normal ~7 to 10 fL; large platelets are nearly as big as an RBC.
• Bleeding history (ISTH-BAT): mucocutaneous pattern (like vWD), epistaxis, gingival bleeding, menorrhagia, postoperative and post-dental bleeding.

Testing for platelet disorders

• Electron microscopy: identifies dense granule deficiencies, Hermansky-Pudlak, delta storage pool disorders, Chediak-Higashi.
• PFA-100: whole blood exposed to a membrane coated with collagen/epinephrine (Col/Epi) or collagen/ADP (Col/ADP); platelet plug closes the aperture (closure time). Useful screen; low sensitivity for primary secretion defects and storage pool disease; does NOT differentiate platelet disorders from vWD; affected by anemia/hematocrit.
• Light transmission aggregometry (LTA): gold standard for platelet aggregation, uses platelet-rich plasma (aggregates → less turbidity → increased light transmission).
  • LTA limitations: not reliable at platelet count <150,000/mm³; affected by platelet size; requires large sample and standardization; mild defects hard to interpret.
  • Whole blood aggregometry: measures change in electrical impedance; more physiologic, less manipulation.
  • VerifyNow: turbidimetric test using ADP or arachidonic acid to measure inhibition from ASA or P2Y12 blockers.
• Flow cytometry: fluorescently labeled antibodies detect glycoprotein and activation-pathway defects. Small sample, uses whole blood, not dependent on platelet count, detects more specific and mild defects. Surface GPIb/IX (Bernard-Soulier), GPIIb/IIIa (Glanzmann), Intracellular WASp in leukocytes (Wiskott-Aldrich), Ia/IIa (collagen receptor defects). After agonist exposure: CD62p (P-selectin) for alpha granule release, CD63 for dense granule release. Also used for anti-platelet drug testing and transfusion medicine.
• Thromboelastography (TEG) and platelet mapping: platelet mapping is a TEG modification measuring platelet aggregation to ADP or arachidonic acid, reported as percent inhibition. Designed for monitoring antiplatelet therapy, NOT diagnostic for inherited platelet disorders; may help peri-operatively.
• Genetic testing: high-throughput sequencing for single-nucleotide variants (separate testing for copy-number/gross rearrangements). British Society of Haematology: offer genetic analysis to all patients suspected of a hereditary platelet disorder; an HTS panel should include all ISTH-listed causative genes; counsel on variants of uncertain significance and incidental findings. May be avoidable if other tests confirm the diagnosis; impacts family planning and management.

Aggregometry: agonists and patterns

• Agonists and behavior:
  • Epinephrine: most unreliable of all agonists.
  • ADP: biphasic response (second wave ↓ by P2Y12 inhibitors).
  • Collagen: strongest agonist used in testing.
  • Ristocetin: causes GPIb/vWF-dependent platelet agglutination (not true aggregation).
  • Arachidonic acid: converted to thromboxane A2 by COX; AA wave is ↓↓↓ with ASA (COX inhibited).

Inherited qualitative platelet disorders

• Glanzmann thrombasthenia: ITGA2B/ITGB3 (GPIIb/IIIa) defect → absent fibrinogen-mediated aggregation. Autosomal recessive (no bleeding in heterozygotes). Severe mucocutaneous bleeding from infancy; normal platelet count and size. GT is second in the alphabet → defect in GPIIb/IIIa. Diagnosed younger than Bernard-Soulier. LTA: absent aggregation to ALL agonists EXCEPT ristocetin; impaired clot retraction; normal PT/PTT/TT (afibrinogenemia gives identical aggregation but abnormal TT). Dx by flow cytometry (decreased GPIIb/IIIa in classic GT; variant GT may express near-normal but dysfunctional receptor), confirmed with aggregometry, clot retraction, and ITGA2B/ITGB3 testing. Frequent platelet transfusions → alloimmunization → pregnant patients can have infants with neonatal alloimmune thrombocytopenia. Tx: rFVIIa (NovoSeven) for acute bleeding, antifibrinolytics, HLA-matched platelets if alloimmunized.
• Bernard-Soulier syndrome: GP1BA, GP1BB, GP9 defect (GPIb-IX-V, the vWF receptor) → no vWF binding, no adhesion. Autosomal recessive (little family history). Second-most diagnosed inherited platelet disorder in adults; commonly misdiagnosed as chronic ITP. Macrothrombocytopenia with giant platelets (usually platelets >30K, not extremely low); older patients than Glanzmann. B = Big, GP1B, binds von Willebrand factor (ristocetin-enhanced). Absent ristocetin agglutination NOT corrected by normal plasma (vs vWD which corrects); normal ADP/epi/collagen. Tx similar to Glanzmann.
• GPVI deficiency: congenital or acquired defect of the platelet collagen receptor. Rare; absent aggregation to collagen (even high concentration). Inherited GP6 deficiency: isolated collagen-response defect, usually mild bleeding, normal count. Acquired (anti-GPVI autoantibodies, often with ITP or autoimmune disease): may have mild thrombocytopenia and more variable (mild-to-severe) bleeding.
• LAD-III (leukocyte adhesion deficiency III): rare AR syndrome from defective integrin activation (FERMT3/kindlin-3). Affects leukocytes and platelets → severe bacterial infections + bleeding (Glanzmann-like defect with intact integrin expression). Tx: HSCT. A RASGRP2 variant (CalDAG-GEFI deficiency) causes abnormal GPIIb/IIIa signaling and a Glanzmann-like defect.
• Wiskott-Aldrich syndrome (WAS): X-linked, WAS gene (WASP, an actin-cytoskeleton reorganization protein). Triad plus: thrombocytopenia + small platelets + eczema + immunodeficiency, plus autoimmunity and increased lymphoma/malignancy. Loss-of-function → classic WAS and X-linked thrombocytopenia; gain-of-function → X-linked neutropenia. Tx: supportive (prophylactic antimicrobials, platelet transfusion, IVIG); allo-HSCT is curative; autologous gene therapy (etuvetidigene autotemcel, Waskyra) FDA approved December 2025 for patients 6 months and older without a suitable HLA-matched related donor. X-linked thrombocytopenia (XLT) is a milder variant (congenital microthrombocytopenia, mild eczema, near-normal life expectancy).
• MYH9-related disorders (formerly May-Hegglin, Sebastian, Fechtner, Epstein): autosomal dominant (~30% de novo), MYH9 encodes nonmuscle myosin IIA → weak cytoskeleton contraction, reduced clot stability. Macrothrombocytopenia + Dohle-body-like leukocyte inclusions. Variable: sensorineural hearing loss, nephritis/renal failure, cataracts. Bleeding usually mild to moderate (platelet function nearly normal).
• Hermansky-Pudlak syndrome: HPS1, 3, 4, 5, 6 and others (all AR). Dense-granule storage pool defect → loss of the ADP second wave. Oculocutaneous albinism + bleeding + granulomatous colitis + pulmonary fibrosis (HPS1, HPS4; lung transplant clue). Increased reticuloendothelial ceroid, congenital nystagmus, reduced visual acuity. Affects 1 in 1,800 in northwest Puerto Rico. Confirm with EM and nucleotide-release studies.
• Chediak-Higashi syndrome: AR, LYST/CHS1 (BEACH-family vesicle-trafficking protein) → giant dysfunctional inclusion bodies. Partial albinism + immunodeficiency (impaired chemotaxis/phagolysosome function) + mild bleeding + neurologic defects; most progress to an accelerated (HLH-like) phase. Tx: supportive; allo-HSCT in severe cases.
• Gray platelet syndrome (NBEAL2): absent alpha granules → washed-out (gray) platelets on light microscopy; dense granules generally preserved. Moderate thrombocytopenia, mild-to-moderate bleeding. Progressive thrombocytopenia, myelofibrosis, splenomegaly, elevated serum B12. Mostly AR (NBEAL2, chromosome 3p21); an AD form is linked to GFI1B.
• Griscelli syndrome: melanosome-transport disorder with partial albinism; RAB27A (type 2) causes HLH susceptibility, not a characteristic platelet dense-granule bleeding disorder.
• Storage pool disease (delta granule): dense-granule deficiency; mild-moderate bleeding; LTA shows reduced second-wave aggregation.
• Quebec platelet disorder: tandem duplication of PLAU → excess urokinase (uPA) in alpha granules → premature intra-platelet fibrinolysis and depletion of platelet Factor V (about 20% of total blood FV is stored in platelet alpha granules). Mild thrombocytopenia; delayed bleeding 12 to 24 h after surgery/dental work; poor wound healing; heavy menstrual bleeding. Dx: platelet FV/fibrinogen/uPA analysis, genetics. Tx: peri-procedural TXA or aminocaproic acid.
• Platelet-type vWD: gain-of-function GP1BA (GPIb-alpha) → excessive platelet-vWF binding → thrombocytopenia and loss of HMW multimers. Abnormal RIPA (increased to low-dose ristocetin) with loss of HMW multimers; mimics type 2B vWD.
• Familial platelet disorder with predisposition to AML: RUNX1 (AD) → thrombocytopenia/platelet dysfunction with leukemia risk. Other transcription-factor disorders: GATA1 (X-linked thrombocytopenia with dyserythropoiesis), FLI1 (Paris-Trousseau/Jacobsen), GFI1B.
• Scott syndrome: TMEM16F (ANO6) defect → impaired platelet phospholipid scrambling (defective procoagulant surface exposure).

Functional classification of inherited platelet disorders

• Adhesion defects: vWD or platelet-type vWD; Bernard-Soulier syndrome; GPVI deficiency (collagen response).
• Aggregation defects: Glanzmann thrombasthenia; Glanzmann-like disorders; LAD-III; congenital afibrinogenemia (no plasma fibrinogen).
• Storage pool diseases: dense granule (Hermansky-Pudlak, Chediak-Higashi); alpha granule (gray platelet syndrome, Quebec platelet disorder, arthrogryposis-renal dysfunction-cholestasis [ARC] syndrome).
• Cytoskeletal / structural protein defects: Wiskott-Aldrich; filamin (FLNA); (TUBB1, ACTN1, MYH9 not typically associated with major dysfunction).
• Transcription factor abnormalities: RUNX1, GATA1, FLI1 (Paris-Trousseau), GFI1B.
• Receptor and signaling defects: G proteins (Gaq, Gai2, Gas); effector enzymes (phospholipase C-β2, PKC-theta); receptor defects of ADP (P2Y12), thromboxane A2, GPVI, GPIa/IIa.

Acquired platelet dysfunction

• Antiplatelet drugs (most common cause): aspirin (irreversible COX-1, effect ~7 to 10 days; detectable within 1 h); clopidogrel/prasugrel/ticagrelor (P2Y12 inhibitors); GPIIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban); dipyridamole and cilostazol (PDE inhibitors); vorapaxar (PAR1); SSRIs.
• Uremia / chronic renal disease: platelet dysfunction independent of platelet count via multiple mechanisms:
  • Adhesion defect (rationale for desmopressin benefit).
  • Decreased secretion: impaired arachidonic acid/prostaglandin metabolism, altered endothelial NO and PGI2.
  • Storage pool defect: reduced dense-granule ADP and serotonin (platelet activation during dialysis); TXA2 generation is impaired separately via the COX pathway.
  • GPIIb/IIIa signaling defect: impaired fibrinogen binding (circulating guanidinosuccinate / Arg-Gly-Asp peptides).
  • Management: dialysis (HD or PD, most effective); DDAVP (↑ vWF, shortens bleeding time in 50 to 75%); cryoprecipitate; raise hematocrit with RBC transfusion and EPO; conjugated estrogens (IV or oral, slower onset, longer-lasting). Transfused platelets acquire the same defect, so more may be needed.
• Liver disease: thrombocytopenia (76% mild-moderate in cirrhosis, 13% severe <50K) plus dysfunction (↓ TXA2 synthesis, storage pool deficiency, GPIb defect), anemia contribution; also 10 to 20% portal vein thrombosis and embolic risk. Lusutrombopag and avatrombopag can raise platelets before a procedure (e.g., TIPS).
• Bone marrow disease: MPN, MDS (abnormal aggregation to several agonists, especially collagen; granule defects), leukemias, dysproteinemias.
• MPN (ET, PV): extreme thrombocytosis >1M → acquired vWF syndrome (large platelets adsorb HMW vWF) → paradoxical bleeding; cytoreduce.
• Multiple myeloma / dysproteinemia: paraprotein coats platelets → dysfunction.
• Cardiopulmonary bypass / VAD: platelet activation and granule loss → acquired storage pool deficiency; acquired loss of HMW vWF multimers; increased thrombosis risk; transient post-op dysfunction.
• Severe aortic stenosis (Heyde syndrome): shear-induced loss of HMW vWF multimers + GI angiodysplasia bleeding; resolves after aortic valve replacement.
• Medications (non-antiplatelet): NSAIDs (reversible COX inhibition; do not combine with aspirin); high-dose penicillins (nafcillin) and cephalosporins (moxalactam, cefotaxime), nitrofurantoin; cardiovascular drugs (beta-blockers, nitrates, verapamil, quinidine, statins, dextrans); psychotropics (SSRIs, TCAs, phenothiazines); anesthetics; chemotherapy (mithramycin, BCNU, daunorubicin, MEK/tyrosine kinase/JAK inhibitors, ibrutinib [BTK]); radiographic contrast; dietary (vitamin E, fish oil, garlic, ginger, turmeric, ethanol).

High yield

• Glanzmann: GPIIb/IIIa defect; LTA fails ALL agonists except ristocetin; normal count/size; younger than BSS.
• Bernard-Soulier: GPIb defect; macrothrombocytopenia with giant platelets; absent ristocetin NOT corrected by normal plasma (vs vWD which corrects).
• vWD vs BSS on aggregometry: add normal plasma; vWD corrects, BSS does not.
• Wiskott-Aldrich: X-linked thrombocytopenia + small platelets + eczema + immunodeficiency.
• Hermansky-Pudlak: albinism + bleeding + pulmonary fibrosis (HPS1/4); loss of ADP second wave.
• Gray platelet syndrome: absent alpha granules; myelofibrosis, splenomegaly, high B12.
• MYH9-related: macrothrombocytopenia + Dohle-like leukocyte inclusions, plus/minus nephritis/deafness/cataracts.
• Quebec platelet disorder: PLAU duplication, delayed bleeding, treat with antifibrinolytics.
• Aspirin irreversibly inhibits COX-1; effect lasts ~7 to 10 days; arachidonic acid wave absent.
• Uremia: dialyze, DDAVP, cryoprecipitate, conjugated estrogens, raise hematocrit.
• AVWS in MPN with platelets >1M: cytoreduce.
• Platelet mapping / VerifyNow: monitor antiplatelet therapy, NOT for diagnosing inherited disorders.